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1.
Front Endocrinol (Lausanne) ; 14: 1268135, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38027095

RESUMO

Timely diagnosis of persistent neonatal hypoglycemia is critical to prevent neurological sequelae, but diagnosis is complicated by the heterogenicity of the causes. We discuss two cases at separate institutions in which clinical management was fundamentally altered by the results of molecular genetic testing. In both patients, critical samples demonstrated hypoketotic hypoglycemia and a partial glycemic response to glucagon stimulation, thereby suggesting hyperinsulinism (HI). However, due to rapid genetic testing, both patients were found to have deoxyguanosine kinase (DGUOK)-related mitochondrial DNA depletion syndrome, an unexpected diagnosis. Patients with this disease typically present with either hepatocerebral disease in the neonatal period or isolated hepatic failure in infancy. The characteristic features involved in the hepatocerebral form of the disease include lactic acidosis, hypoglycemia, cholestasis, progressive liver failure, and increasing neurologic dysfunction. Those with isolated liver involvement experience hepatomegaly, cholestasis, and liver failure. Although liver transplantation is considered, research has demonstrated that for patients with DGUOK-related mitochondrial DNA depletion syndrome and neurologic symptoms, early demise occurs. Our report advocates for the prompt initiation of genetic testing in patients presenting with persistent neonatal hypoglycemia and for the incorporation of mitochondrial DNA depletion syndromes in the differential diagnosis of HI.


Assuntos
Colestase , Hiperinsulinismo , Hipoglicemia , Falência Hepática , Humanos , Recém-Nascido , DNA Mitocondrial/genética , Hipoglicemia/complicações , Hipoglicemia/diagnóstico , Hipoglicemia/genética , Falência Hepática/genética , Mutação
2.
Public Health Rep ; 135(1_suppl): 57S-64S, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735188

RESUMO

OBJECTIVES: California is experiencing a syphilis and congenital syphilis epidemic, and many persons diagnosed with syphilis report a history of recent incarceration or sexual contact with a person who has recently been incarcerated. Fresno County's local health department and jail collaborated to implement a routine syphilis screening policy for male adults aged 18-30 and female adults aged 18-35 booked into the facility. We evaluated syphilis screening, case finding, and treatment rates after implementation of the new policy. METHODS: We linked jail census and laboratory data to syphilis surveillance data to assess screening coverage, positivity, and treatment rates for age-eligible persons who were booked into Fresno County Jail from April 1, 2016, through December 31, 2017. RESULTS: Of 24 045 age-eligible persons who were booked into the jail during the study period, 5897 (24.5%) were female and 18 148 (75.5%) were male. Of 7144 (29.7%) persons who were screened for syphilis, 611 (8.6%) had a reactive rapid plasma reagin blood test result (16.4% [253 of 1546] of female adults; 6.4% [358 of 5598] of male adults) and 238 (3.3%) were newly diagnosed with syphilis, as confirmed by matching to the surveillance system (6.9% [106 of 1546] of female adults; 2.4% [132 of 5598] of male adults). Of persons identified with syphilis, 51.7% (n = 123 of 238) received adequate recommended treatment (59.4% [63 of 106] of female adults; 45.5% [60 of 132] of male adults). CONCLUSIONS: The age-based syphilis screening policy adopted in this jail yielded high positivity, including newly identified syphilis infections among female adults of childbearing age. The targeted screening policy was formalized in the county-negotiated contract with the jail's private correctional health care company in 2018-a strategy that can be replicated.


Assuntos
Programas de Rastreamento/organização & administração , Prisões/organização & administração , Sífilis/diagnóstico , Sífilis/epidemiologia , Adolescente , Adulto , California/epidemiologia , Feminino , Humanos , Incidência , Masculino , Desenvolvimento de Programas , Avaliação de Programas e Projetos de Saúde , Fatores de Risco , Adulto Jovem
3.
J Neurotrauma ; 34(2): 487-494, 2017 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-27321815

RESUMO

Traumatic brain injury (TBI) results in oxidative stress and calcium dysregulation in mitochondria. However, little work has examined perturbations of mitochondrial homeostasis in peri-injury tissue. We examined mitochondrial homeostasis after a unilateral controlled cortical impact over the sensorimotor cortex in adult male rats. There was a significant reduction in peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) messenger RNA (mRNA) at post-injury days 3 and 6 and a transient reduction in mitochondrial DNA copy number at 3 days post-injury that recovered by 6 days in the ipsi-injury striatum. In ipsilateral cortex, PGC-1α mRNA was reduced only at 6 days post-injury. Additionally, expression of mitochondrial-encoded mRNAs, cytochrome c oxidase subunit 1 and NADH dehydrogenase subunit 1, was decreased at 3 and 6 days post-injury in ipsilesional striatum and at 6 days post-injury in ipsilesional cortex. There was no observable decrease in nuclear-encoded mRNAs mitochondrial transcription factor A or NADH dehydrogenase (ubiquinone) Fe-S protein 1. We detected an acute increase in superoxide dismutase 2 mRNA expression, as well as an induction of microRNA (miR)-21 and miR-155, which have been previously demonstrated to disrupt mitochondrial homeostasis. Behaviorally, rats with TBI exhibited marked error rates in contrainjury forelimb performance on the ladder test. These findings reveal that there may be differential susceptibilities of various peri-injury brain structures to mitochondrial dysfunction and associated behavioral deficits, and that molecular pathways demonstrated to interfere with mitochondrial homeostasis and function are activated subacutely post-TBI.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Corpo Estriado/metabolismo , Mitocôndrias/metabolismo , Córtex Sensório-Motor/lesões , Córtex Sensório-Motor/metabolismo , Índice de Gravidade de Doença , Animais , Lesões Encefálicas Traumáticas/genética , Masculino , Mitocôndrias/genética , Ratos , Ratos Long-Evans
4.
J Pharmacol Exp Ther ; 357(1): 1-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26787771

RESUMO

In acute organ injuries, mitochondria are often dysfunctional, and recent research has revealed that recovery of mitochondrial and renal functions is accelerated by induction of mitochondrial biogenesis (MB). We previously reported that the nonselective 5-HT2 receptor agonist DOI [1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine] induced MB in renal proximal tubular cells (RPTCs). The goal of this study was to determine the role of 5-HT2 receptors in the regulation of mitochondrial genes and oxidative metabolism in the kidney. The 5-HT2C receptor agonist CP-809,101 [2-[(3-chlorophenyl)methoxy]-6-(1-piperazinyl)pyrazine] and antagonist SB-242,084 [6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride] were used to examine the induction of renal mitochondrial genes and oxidative metabolism in RPTCs and in mouse kidneys in the presence and absence of the 5-HT2C receptor. Unexpectedly, both CP-809,101 and SB-242,084 increased RPTC respiration and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) mRNA expression in RPTCs at 1-10 nM. In addition, CP-809,101 and SB-242,084 increased mRNA expression of PGC-1α and the mitochondrial proteins NADH dehydrogenase subunit 1 and NADH dehydrogenase (ubiquinone) ß subcomplex 8 in mice. These compounds increased mitochondrial genes in RPTCs in which the 5-HT2C receptor was downregulated with small interfering RNA and in the renal cortex of mice lacking the 5-HT2C receptor. By contrast, the ability of these compounds to increase PGC-1α mRNA and respiration was blocked in RPTCs treated with 5-HT2A receptor small interfering RNA or the 5-HT2A receptor antagonist eplivanserin. In addition, the 5-HT2A receptor agonist NBOH-2C-CN [4-[2-[[(2-hydroxyphenyl)methyl]amino]ethyl]-2,5-dimethoxybenzonitrile] increased RPTC respiration at 1-100 nM. These results suggest that agonism of the 5-HT2A receptor induces MB and that the classic 5-HT2C receptor agonist CP-809,101 and antagonist SB-242,084 increase mitochondrial genes and oxidative metabolism through the 5-HT2A receptor. To our knowledge, this is the first report that links 5-HT2A receptor agonism to mitochondrial function.


Assuntos
Mitocôndrias/genética , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/genética , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Aminopiridinas/farmacologia , Animais , Complexo I de Transporte de Elétrons/biossíntese , Complexo I de Transporte de Elétrons/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Indóis/farmacologia , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias/efeitos dos fármacos , Oxirredução , Consumo de Oxigênio , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Piperazinas/farmacologia , Pirazinas/farmacologia , Coelhos , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Receptor 5-HT2C de Serotonina/genética , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética
5.
Kidney Int ; 88(6): 1336-1344, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26287315

RESUMO

Recent studies show the importance of mitochondrial dysfunction in the initiation and progression of acute kidney injury (AKI). However, no biomarkers exist linking renal injury to mitochondrial function and integrity. To this end, we evaluated urinary mitochondrial DNA (UmtDNA) as a biomarker of renal injury and function in humans with AKI following cardiac surgery. mtDNA was isolated from the urine of patients following cardiac surgery and quantified by quantitative PCR. Patients were stratified into no AKI, stable AKI, and progressive AKI groups based on Acute Kidney Injury Network (AKIN) staging. UmtDNA was elevated in progressive AKI patients and was associated with progression of patients with AKI at collection to higher AKIN stages. To evaluate the relationship of UmtDNA to measures of renal mitochondrial integrity in AKI, mice were subjected to sham surgery or varying degrees of ischemia followed by 24 h of reperfusion. UmtDNA increased in mice after 10-15 min of ischemia and positively correlated with ischemia time. Furthermore, UmtDNA was predictive of AKI in the mouse model. Finally, UmtDNA levels were negatively correlated with renal cortical mtDNA and mitochondrial gene expression. These translational studies demonstrate that UmtDNA is associated with recovery from AKI following cardiac surgery by serving as an indicator of mitochondrial integrity. Thus UmtDNA may serve as valuable biomarker for the development of mitochondrial-targeted therapies in AKI.

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